In order to account for the remarkable catalytic power of enzymes, it is generally considered that the activation free energy (the energy hill which must be surmounted to get from starting material to product) is contributed both by binding of the substrate to the enzyme (step 1) and by chemical manipulation of the bound substrate (bond-making and breaking, step 2). Popular opinion holds that most of the activation energy is supplied in step 2: We have proposed however, that the overall catalytic process can be explained more reasonably if it is assumed that the first step (binding) contributes a more significant, and sometimes major, share of the activation energy. To support this theory, we have synthesized a large variety of test-tube models which simulate the bound substrate by being frozen into a single, favorable conformation and by having the interacting groups brought into the closest possible juxtaposition (stereopulation control). These compounds undergo intramolecular reactions at rates comparable to those catalyzed by enzymes, sometimes even too fast to measure. Enzymes catalyze many reactions which cannot be observed under mild laboratory conditions. We have shown that our "locked" test-tube analogues can undergo a number of these reactions under physiological conditions of temperature and pH. Thus, one can demonstrate such difficult processes as hydride transfer and displacement of aromatic halogens. The protein raises both the entropic and enthalpic components of the free energy content of the substrate by binding it in a single, rigid conformation. To prove that our model compounds are truly frozen in unique conformations in solution, we have used temperature-variable NMR studies, x-ray crystallography, computer calculations of free energy content and kinetic analysis. Thus, we have found that log k for enhanced cyclization is a function of the Van der Waals size of restricting groups and is independent of electronic effects. More recently, we have initiated efforts to demonstrate that these molecules possess molecular chirality, and that the resolved enantiomers do not racemize at elevated temperatures. Indeed, some of our models show such slow rotation of single bonds (half-life = 20 minutes), that conformational change becomes the rate-limiting step in cyclization.